tbuckley/cabot-search huggingface dataset:
Genomic and immune landscape of ERBB2/ERBB3 alterations in gastroesophageal adenocarcinoma.
Authors: Sarbajit Mukherjee, Elizabeth Mauer, Karyn Ronski, Manish A. Shah
Journal: Journal of Clinical Oncology (2023)

457 Background: HER2/ERBB2 is a known therapeutic target in gastroesophageal adenocarcinoma (GEAC). HER3/ERBB3 is an emerging target in a variety of cancers but less defined in GEAC. Insights into the genomic and immunologic landscape of ERBB2/ERBB3 alterations (ERBB2/3-alt) are required to develop effective treatments. Methods: We analyzed de-identified data from 2,050 GEAC patient tumor samples which underwent next generation sequencing with the Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). Bivariate analyses were performed to compare demographics, immuno-oncology (IO) biomarkers, and co-mutations between ERBB2/3-alt groups. P-values comparing individual co-mutations between groups were adjusted for false discovery. Results: Overall, 17.8% (365/2050) of tumors harbored an ERBB2 or ERBB3-alt, 3 of which had both and were excluded from analyses. Alterations were defined as pathogenic/likely pathogenic mutations, copy number amplifications (CN amp), or copy number loss (CN loss). Tumors were divided into ERBB2 CN amp (n=252, 12.3%), ERBB2 other (CN loss/mutation) (n=71, 3.5%), ERBB3 CN amp (n=17, 0.8%), ERBB3 other (n=22, 1%), and WT (n=1685, 82%) for both. No differences were observed between groups regarding baseline demographics (age of onset, race, ethnicity) aside from the percentage of females (p=0.002). Significant differences in IO markers and the co-occurring genetic alterations were seen. ERBB3 other (N = 22 mutations - No CN loss) had increased TMB, microsatellite instability high (MSI-H), and median neoantigen tumor burden. Conclusions: ERBB2/ERBB3-alt are associated with significant changes in the tumor microenvironment in GEAC. Co-occurring genetic or immunologic alterations can be exploited to develop effective targeted or immune therapies. [Table: see text]
Molecular profiling of gastric neuroendocrine carcinomas.
Authors: Ko Ikegame, Keiichi Hatakeyama, Masanori Terashima, Takashi Sugino, Daisuke Aizawa, Kenichiro Furukawa, Keiichi Fujiya, Yutaka Tanizawa, Etsuro Bando, Ken Yamaguchi
Journal: Journal of Clinical Oncology (2023)

451 Background: Reports of comprehensive genetic analysis of gastric neuroendocrine carcinoma (G-NEC) are limited, and few have described the tumorigenesis of G-NEC. G-NEC usually has NEC and adenocarcinoma components and is considered to have a common origin in gastric adenocarcinoma because these two tumors share common pathogenic mutations and loss of heterozygosity. However, G-NEC without adenocarcinoma also exists, and it may have a different mechanism of tumorigenesis than that of G-NEC with adenocarcinoma. This study aimed to elucidate the tumorigenesis of G-NEC by focusing on the percentage of NEC component, using comprehensive genetic analysis. Methods: Of the 698 patients who had undergone gastrectomy for gastric cancer between January 2014 and March 2019, this study included 13 patients with G-NEC. Comprehensive genetic analysis using whole-exome sequencing, deep sequencing using a target gene panel, and microarray analysis were performed. NEC was classified according to the 2010 WHO classification. G-NEC without an adenocarcinoma component was defined as pure NEC. Results: There were six patients with mixed adeno-neuroendocrine carcinoma (MANEC), four patients with NEC, and three patients with pure NEC. TP53 was detected as the most frequent gene mutation, independent of classification (85%). RB1, ANKRD17, KMT2C, LTBP1, MAATS1, and RYR2 mutations were identified in two of three pure NEC patients but were not detected in other G-NEC patients. Gene expression analysis showed that six key transcripts of importance in NEC tumorigenesis were upregulated in two patients with pure NEC, while they were downregulated in all six MANEC patients. Conclusions: NEC and MANEC with adenocarcinoma components tend to share common pathogenic mutations, but Pure NEC has different genomic and transcriptomic characteristics than other NECs. This suggests that pure NEC has a different mechanism of tumorigenesis than other G-NECs with adenocarcinoma. This is the first study to present a comprehensive genetic analysis of G-NEC, classified by the percentage of NEC components.
Overall survival (OS) in gastrointestinal (GI) neuroendocrine tumors (NETs) based on primary site, stage, and surgery.
Authors: Bahar Laderian, Nicole Farha, Prabhjot Singh Mundi, Wei Wei, Alok A. Khorana, Michelle Kang Kim, Scott Steele, Emre Gorgun, Antonio Tito Fojo, Smitha S. Krishnamurthi
Journal: Journal of Clinical Oncology (2023)

643 Background: There are limited data on the impact of primary site and surgical intervention on long-term outcomes in GI-NETs. We hypothesized that primary site would be associated with differences in stage-specific OS. Methods: In the National Cancer DataBase, using histology codes, we identified 124,081 GI-NETs diagnosed between 2004-2019 in individuals 18 years or older. OS was estimated by the Kaplan-Meier method. Differences in survival based on primary site, stage, and surgical intervention were assessed using a Cox proportional hazards model, accounting for multiple comorbidities, e.g. Charlson-Deyo Comorbidity Index. Results: The most common primary site for GI-NETs was small intestine (33.6%), followed by colon, rectum, pancreas, and stomach comprising 19.8%, 17.5%, 15.5%, and 9.2%, respectively. Patients with stage I-III NETs undergoing surgery had significantly better median OS compared to those without surgery (mOS 197 vs 115 mo., p&lt;0.0001 by log rank test). Patients with stage IV NETs undergoing primary resection also had improved mOS vs those with no surgery (125 vs 54 mo., p&lt;0.0001). For stage I-III patients without surgery, 2-yr and 5-yr survival rates were highest in the rectum and lowest in small intestine ( p&lt;0.0001). Among those with stage I-III with surgery, 2-yr and 5-yr survival rates were also highest in the rectum, and lowest in the biliary system at 89% and 82% ( p&lt;0.0001). In contrast, for stage IV patients without primary resection, 2-yr and 5-yr survival rates were highest among small intestine and lowest in the rectum ( p&lt;0.0001). Among those who had primary tumor resection, 2-yr and 5-yr survival rates were highest in pancreas and lowest in colon at 2 yrs and rectum at 5 yrs ( p&lt;0.0001). Conclusions: Surgical intervention for GI-NETs is associated with improved OS in both localized and stage IV disease, with consistent trends across different primary sites. Primary tumor resection was associated with the largest increase in 5-yr survival for stage IV NETs arising from pancreas and stomach. Patient selection for surgery undoubtedly contributed to the improved OS, but resection of primary tumors in stage IV GI-NETs may have a disease modifying effect. Further study is warranted with more granular data to identify patients with stage IV GI-NETs who may benefit from primary tumor resection.[Table: see text]
Sex differences in the clinicopathological and molecular biological features of gastric cancer.
Authors: Masanori Terashima, Taisuke Yagi, Keiichi Hatakeyama, Kenichiro Furukawa, Keiichi Fujiya, Yutaka Tanizawa, Etsuro Bando, Ken Yamaguchi
Journal: Journal of Clinical Oncology (2023)

421 Background: The prevalence of gastric cancer is higher in males than in females. Reports have revealed that female gastric cancer patients exhibit some distinctive features, such as a high proportion of undifferentiated cancer and poor survival outcomes. The therapeutic effects of anti-PD-1 antibody have also been reported to be different between males and females. However, precise differences in molecular profiling features between males and females are yet to be reported. To elucidate sex differences in the clinicopathological and molecular biological characteristics of gastric cancer, we performed whole-exon sequencing and comprehensive gene expression analysis. Methods: We compared the clinicopathological factors and disease-specific survival (DSS) in 499 patients who underwent gastrectomy for gastric cancer between January 2014 and April 2019, excluding those with special types of gastric cancer and R2 resection. We also performed whole-exome sequencing using peripheral blood and tumor tissue, gene panel testing, and transcriptome analysis of tumor and nontumor tissues. Results: Among the 499 patients, 358 were male and 141 were female. Women had significantly more undifferentiated and M-region cancers (P &lt; 0.05 for both). In terms of gene mutations, TP53 mutations were significantly more common in males (P = 0.002), whereas CDH1 (P = 0.005), PIK3CA (P = 0.046), and ERBB3 (P = 0.021) mutations were significantly more common in females. Expression profiles reflecting the tumor microenvironment were classified into two groups: T cell high group (290 patients) and T cell low group (209 patients), via cluster analysis. Men in the T-cell high group had significantly better DSS than those in the T-cell low group (P = 0.005), whereas no significant difference was observed among women in the T-cell high and low groups (P = 0.402). Among the 136 genes significantly upregulated in the T-cell high group, CCL18 (P = 0.048) gene was significantly upregulated in males and CD8A (P = 0.026) gene was upregulated in females. Conclusions: TP53 mutations were more common in male patients with gastric cancer, whereas CDH1, PIK3CA, and ERBB3 mutations were more common in female patients with gastric cancer. Additionally, women did not demonstrate good survival outcomes even in the T-cell high group considered to have enhanced tumor immunity.
Prognostic factors of multidisciplinary treatment for borderline resectable and locally advanced pancreatic adenocarcinoma: Results of a dual-center study.
Authors: Nana Kimura, Takamichi Igarashi, Suguru Yamada, Kenta Murotani, Isaku Yoshioka, Hideki Takami, Kazuto Shibuya, Masamichi Hayashi, Haruyoshi Tanaka, Katsuhisa Hirano, Toru Watanabe, Nobutake Tanaka, Hayato Baba, Yuuko Tohmatsu, Ayano Sakai, Mina Fukasawa, Koshi Matsui, Tomoyuki Okumura, Yasuhiro Kodera, Tsutomu Fujii
Journal: Journal of Clinical Oncology (2023)

680 Background: Multidisciplinary treatment of borderline resectable (BR)/unresectable locally advanced (UR-LA) pancreatic adenocarcinoma (PDAC) has not yet been established. The purpose of this study is to explore factors that improve prognosis in radical surgery after multidisciplinary treatment for pancreatic cancer. Methods: We evaluated the following prognostic factors in 240 PDAC patients who underwent radical resection after multidisciplinary treatment. Patients were classified into 3 groups according to NCCN guidelines (BR PDAC invading the portal vein (BR-PV), BR pancreatic cancer in contact with the major arteries such as the hepatic artery, celiac axis and superior mesenteric artery (BR-A), and UR-LA), and prognostic factors were investigated. Patients with BR PDAC were treated with chemotherapy followed by surgery, while radiation therapy was added preoperatively in most cases with arterial invasion. All patients with UR-LA underwent surgery after nab-paclitaxel plus gemcitabine (GnP) followed by chemoradiotherapy (CRT) with S-1. Results: BR-PV/BR-A/UR-LA patients were 88/111/41, respectively. Prognosis was significantly better in the NAT group than in the upfront surgery group for both BR-PV/A (P=0.004/&lt;0.001). In univariate analysis of overall survival (OS) in 36 patients with BR-PV who underwent resection after NAT, the following factors were significantly favorable prognostic factors; tumor marker (TM) normalization (P=0.028), preoperative Glasgow prognostic score=0 (P=0.025), and preoperative prognostic nutritional index (PNI)&gt;42.5 (P=0.022). In univariate analysis in 39 patients with BR-A, the following factors were significantly favorable prognostic factors; TM normalization (P=0.033), preoperative PNI&gt;42.5 (P=0.013), intraoperative blood loss&gt;830 ml (P=0.013). Multivariate analysis revealed that high preoperative PNI was an independent prognostic factor (hazard ratio 0.15 [0.02-0.85]; P=0.014) in BR-A patients. In patients with UR-LA who underwent radical resection after GnP and subsequent CRT, median duration of NAT was 8.8 months, and R0 resection was achieved in 36 patients (88%). 3-year OS was 77.4%, and 5-year OS 58.6%. Multivariate analysis revealed that CA19-9 normalization (hazard ratio 0.23 [0.02-0.88]; P=0.032) and PNI≥41.7 (HR 0.05 [0.01-0.62]; P=0.021) were independent prognostic factors. Conclusions: In both BR/UR-LA pancreatic cancer, normalization of TM and maintenance of good nutritional status during NAT until surgery may contribute to prolonged prognosis.
Tislelizumab versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: Impact on health-related quality of life in RATIONALE-301 population.
Authors: Richard S. Finn, Shukui Qin, Masatoshi Kudo, Tim Meyer, Frederic Boisserie, Songzi Li, Yaxi Chen, Gisoo Barnes, Ramil Abdrashitov, Andrew X. Zhu, Arndt Vogel
Journal: Journal of Clinical Oncology (2023)

495 Background: RATIONALE-301 (NCT03412773), a global Phase 3 study, comparing tislelizumab (TIS) to sorafenib (SOR) as 1L treatment in adult patients (pts) with unresectable HCC (uHCC), met its primary endpoint of OS non-inferiority. This analysis examined the HRQoL outcomes in pts in both arms. Methods: Systemic therapy-naïve adults with histologically confirmed uHCC were randomized 1:1 to receive TIS (200 mg IV Q3W, n=342) or SOR (400 mg PO BID, n=332). HRQoL was assessed using EORTC QLQ-C30, QLQ-HCC18 and EQ5D-5L. A mixed model for repeated measures using key pre-specified PRO endpoints of global health status/quality of life (GHS/QoL), physical functioning and fatigue scales of the QLQ-C30, and HCC18 index score, fatigue and pain scores at the key pre-specified clinical cycles 4 and 6 were performed. Time to deterioration was examined with the Kaplan-Meier method using the PRO endpoints. Results: At both cycles, TIS had better HRQoL outcomes than SOR, as indicated by LS mean differences in GHS/QoL, physical functioning, fatigue and HCC symptom index, but not for pain. TIS had a lower risk for deterioration of QLQ-C30 GHS/QoL (hazard ratio [HR] 0.68 [95% CI, 0.49-0.94]), physical functioning (0.53 [0.39-0.73]) and fatigue (0.48 [0.37, 0.63]) as well as for deterioration in the HCC18 index (0.53 [0.34-0.81]) and fatigue (0.60 [0.46-0.80]). Both arms had a similar risk for deterioration in pain (HR 0.78 [0.56-1.09]). TIS maintained while SOR declined EQ-5D-5L VAS (general health status) scores at cycle 4 (mean change from baseline =-0.4 [SD = 14.52] vs -4.3 [12.92]) and cycle 6 (-0.2 [17.03] vs -5.4 [13.09]). Conclusions: Pts with HCC treated with 1L TIS had better HRQoL outcomes compared with pts treated with SOR, particularly in terms of fatigue and physical functioning. These results, along with effects an overall survival, response rate, and a favorable safety profile, support the benefit of TIS as a potential 1L treatment option for uHCC. Clinical trial information: NCT03412773 .[Table: see text]
Differences in tumor-associated T cell receptor repertoires between young-onset and average-onset colorectal cancer.
Authors: Stephanie Schmit, Ya-Yu Tsai, Kanika G. Nair, Shimoli V Barot, Shao Xiang, Suneel Deepak Kamath, Marilena Melas, Christopher P Walker, Raghvendra Srivastava, Timothy An-thy Chan, Joseph D. Bonner, Kevin McDonnell, Gregory Idos, Joel K Greenson, Hedy S Rennert, Gad Rennert, Stephen B. Gruber, Alok A. Khorana, David Liska
Journal: Journal of Clinical Oncology (2023)

207 Background: The incidence of colorectal cancer (CRC) among individuals younger than age 50 (young-onset CRC; YOCRC) has increased, yet the etiology and molecular mechanisms underlying this alarming rise remain unclear. Some studies suggest that YOCRCs have more aggressive biology. Here, we compare tumor-associated T cell repertoires between patients with YOCRC and average-onset CRC (AOCRC). A robust, focused T cell response is a positive prognostic indicator; therefore, we hypothesized that YOCRCs demonstrate lower T cell abundance and greater T cell diversity than AOCRCs. Methods: The discovery cohort included 242 patients with histologically confirmed Stage I-IV CRC who underwent surgical resection at Cleveland Clinic from 2000 to 2020 and consented to a biorepository. YOCRC was defined as &lt; 50 years at diagnosis (N = 126), and AOCRC as &gt; 60 years (N = 116). DNA was extracted from frozen tumors, and T Cell Receptor (TCR) abundance and clonality were measured using immunoSEQ (Adaptive Biotechnologies). Following quality control, logistic regression models were used to evaluate the associations between TCR repertoire features and age of onset, adjusting for sex, race, tumor location, and stage. Findings were replicated in 152 YOCRC and 1,984 AOCRC cases from the Molecular Epidemiology of Colorectal Cancer Study with adjustment for sex, Jewish ethnicity, tumor location, and stage. Results: YOCRC patients were more likely to have left-sided tumors and be diagnosed at advanced stages in both cohorts. In the discovery cohort, YOCRC tumors had significantly lower TCR clonality (higher T cell diversity) compared to AOCRC tumors in a multivariable model adjusting for sex, race, tumor location and stage (OR: 0.38, 95% Confidence Interval (CI): 0.25-0.56, p &lt; 0.0001). This association was also observed in the replication cohort (OR: 0.74, 95% CI: 0.62-0.89, p = 0.0013). In the replication cohort, further adjustment for microsatellite instability status did not substantially change the association (OR: 0.73, 95% CI: 0.61-0.88 p = 0.0012). When restricting to microsatellite stable tumors, clonality remained statistically significant in both the discovery and replication cohorts. No significant difference in TCR abundance was observed between YOCRC and AOCRC in either cohort. Conclusions: Higher T cell repertoire diversity, indicating a less focused intratumoral T cell response, is more frequently observed in YOCRC. Further studies are warranted to investigate the role of T cell diversity in the etiology and outcomes of YOCRC.
A phase 2 study of durvalumab plus DOS (docetaxel, oxaliplatin, S-1) neoadjuvant chemotherapy followed by surgery and adjuvant durvalumab plus S-1 chemotherapy in patients with resectable locally advanced gastric cancer: An interim efficacy report.
Authors: Hyung-Don Kim, Min-Hee Ryu, Young Soo Park, Jong Seok Lee, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2023)

408 Background: The phase 3 PRODIGY study showed that neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy, as part of perioperative chemotherapy, was effective and tolerable in Asian patients with resectable locally advanced gastric cancer (LAGC). The current study aimed to evaluate the efficacy and safety of neoadjuvant durvalumab plus DOS, which was followed by surgery and adjuvant durvalumab plus S-1 chemotherapy in patients with resectable LAGC. Methods: In this single-center, open-label, phase II study, patients with locally advanced gastric or gastroesophageal junction cancer (i.e., cT2/3N+ or cT4Nany) were enrolled. In patients with proficient mismatch repair protein (pMMR) tumors (main arm), 3 cycles of neoadjuvant durvalumab plus DOS were administered every 3 weeks, which was followed by surgery and adjuvant S-1 plus durvalumab administered every 6 weeks for 12 months. The primary endpoints were the rate of pathologic complete regression (pCR) and the safety. For an exploratory purpose, patients with deficient mismatch repair protein tumors (exploratory arm) were treated with 3 cycles of neoadjuvant durvalumab and tremelimumab every 4 weeks followed by surgery and adjuvant durvalumab administered every 4 weeks for 12 months. At this interim analysis, we report the results of patients with pMMR. Results: As of SEP 2022, 40 subjects with pMMR were enrolled and received ≥ 1 dose of neoadjuvant treatment. Thirty-five subjects completed 3 cycles of neoadjuvant treatment, and 31 received surgery as of the data cut-off. Among 31 patients who received surgery, a pCR was confirmed in 9 (29.0%), meeting the primary efficacy endpoint (8 pCR out of 40) early. Among those who received 3 cycles of neoadjuvant treatment, 3 (8.6%) experienced the predefined unacceptable severe toxicities during the neoadjuvant treatment: febrile neutropenia (n=2) and G4 neutropenia persisted for ≥ 7 days (n=1). Conclusions: The current study met its primary efficacy endpoint and is expected to meet the primary safety endpoint (&lt;20%). Neoadjuvant durvalumab plus DOS followed by surgery and adjuvant durvalumab plus S-1 chemotherapy deserves to be investigated in a phase 3 trial in Asian patients with LAGC. Clinical trial information: 04221555 .
Serum trefoil factor family 3 as a biomarker for the detection of colorectal cancer.
Authors: Hyun Seok Lee
Journal: Journal of Clinical Oncology (2023)

229 Background: Colorectal cancer is one of the most frequent causes of cancer-related deaths worldwide. Thus, there is a need for timely diagnosis and effective treatment. Our aim in the present study was to detect the serum level of trefoil factor family 3 (TFF3) and evaluate the diagnostic accuracy of TFF3 in patients with colorectal cancer. Methods: We prospectively collected serum samples from 72 subjects (36 patients with colorectal cancer and 36 healthy controls) in the derivation cohort. The validation cohort prospectively included 70 subjects (35 patients with colorectal cancer and 35 healthy controls). The levels of serum TFF3 and carcinoembryonic antigen (CEA) were examined using enzyme-linked immunosorbent assay. Results: The serum levels of TFF3 in patients with colorectal cancer was significantly higher compared with that in the healthy controls (9.34±12.2 ng/mL vs. 3.60±1.58 ng/mL, P = 0.008) in the derivation cohort. Using a cutoff of 3.85 ng/mL in the derivation cohort, the sensitivity, specificity, and area under the curve of serum TFF3 for the detection of advanced colorectal cancer were 0.972, 0.611, and 0.875, respectively. The sensitivity of serum TFF3 for the detection of colorectal cancer was superior (97.2%) to that of CEA (36.1%) in the derivation cohort. In the validation cohort, the sensitivity, specificity, and area under the curve of serum TFF3 for the detection of colorectal cancer were 0.771, 0.486, and 0.751, respectively. Similarly, the sensitivity of serum TFF3 for the detection of colorectal cancer was also superior (77.1%) to that of CEA (22.9%) in the validation cohort. Conclusions: Serum TFF3 is a potential biomarker for the detection of colorectal cancer and is more effective compared with CEA.